Small volume resuscitation with HyperHaes improves pericontusional perfusion and reduces lesion volume following controlled cortical impact injury in rats.
ABSTRACT The hyperosmolar and hyperoncotic properties of HyperHaes (HHES) might improve impaired posttraumatic cerebral perfusion. Possible beneficial effects on pericontusional perfusion, brain edema, and contusion volume were investigated in rats subjected to controlled cortical impact (CCI). Male Sprague-Dawley rats (n = 60) anesthetized with isoflurane were subjected to a left temporoparietal CCI. Thereafter, rats were randomized to receive HHES (10% hydroxyethylstarch, 7.5% NaCl) or physiological saline solution (4 mL/kg body weight) intravenously. Mean arterial blood pressure (MABP) and intracranial pressure (ICP) were determined before and following CCI, after drug administration and 24 h later. Regional pericontusional cortical perfusion was determined by scanning laser Doppler flowmetry before CCI, and 30 min, 4 and 24 h after injury. At 24 h brain swelling and water content were measured gravimetrically. At 7 days, cortical contusion volume was determined planimetrically. MABP was not influenced by HHES. ICP was significantly decreased immediately after HHES infusion (5.7 +/- 0.4 vs. 7.1 +/- 1.0 mm Hg; p < 0.05). Pericontusional cortical perfusion was significantly decreased by 44% compared to pre-injury levels (p < 0.05). HHES significantly improved cortical perfusion at 4 h after CCI, approaching baseline values (85 +/- 12%). While increased posttraumatic brain edema was not reduced by HHES at 24 h, cortical contusion volume was significantly decreased in the HHES-treated rats at 7 days after CCI (23.4 +/- 3.5 vs. 39.6 +/- 6.2 mm3; p < 0.05). Intravaneous administration of HHES within 15 min after CCI has a neuroprotective potential, as it significantly attenuated impaired pericontusional perfusion and markedly reduced the extent of induced structural damage.
- SourceAvailable from: benthamscience.comThe Open Critical Care Medicine Journal 01/2009; 2(1):18-27.
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ABSTRACT: Effective methods for treating cerebral edema have recently become a matter of both extensive research and significant debate within the neurosurgery and trauma surgery communities. The pathophysiologic progression and outcome of different forms of cerebral edema associated with traumatic brain injury have yet to be fully elucidated. There are heterogeneous factors influencing the onset and progress of post-traumatic cerebral edema, including the magnitude and type of head injury, age, co-morbid conditions of the patient, the critical window for therapeutic intervention and the presence of secondary insults including hypoxia, hypotension, hypo/hyperthermia, degree of raised intracranial pressure (ICP), and disruption of blood brain barrier (BBB) integrity. Although numerous studies have been designed to improve our understanding of the etiology of post-traumatic cerebral edema, therapeutic interventions have traditionally been focused on minimizing secondary insults especially raised ICP and improving cerebral perfusion pressure. More recently, fluid resuscitation strategies using hyperosmolar agents such as pentastarch and hypertonic saline (HS) have achieved some success. HS treatment is of particular interest due to its apparent advantageous action over other types of hyper-osmotic solutions in both clinical and laboratory studies. In this review, we provide a summary of recent literature concerning the pathogenesis and mechanisms involved in the various types of cerebral edema, and the possible mechanisms of action of HS for the treatment cerebral edema.European Journal of Trauma and Emergency Surgery 34(4):397-409. · 0.26 Impact Factor
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ABSTRACT: Everyone interested in neuroanaesthesia talks about intracranial pressure (ICP), but in daily clinical practice nobody measures it during craniotomy. This was the thesis that started this work more than ten years ago. A method for easy monitoring of ICP during surgery, but before opening of dura, was devised and the method was introduced in our daily clinical practice. In this chapter indications for ICP measurement, critical levels of ICP and regional differences in ICP are described. Medical approaches to ICP control are considered, including body position, hyperventilation, hypothermia and administration of barbiturate. The effect of suctioning, positive end-expiratory pressure, sedatives and analgetics are discussed as well as the use of mannitol and hypertonic saline.
JOURNAL OF NEUROTRAUMA
Volume 21, Number 12, 2004
© Mary Ann Liebert, Inc.
Small Volume Resuscitation with HyperHaes™ Improves
Pericontusional Perfusion and Reduces Lesion Volume
following Controlled Cortical Impact Injury in Rats
ULRICH-WILHELM THOMALE, MARTIN GRIEBENOW,1
STEFAN-NIKOLAUS KROPPENSTEDT,1ANDREAS W. UNTERBERG,1,2
and JOHN F. STOVER1,3
The hyperosmolar and hyperoncotic properties of HyperHaesTM(HHES) might improve impaired
posttraumatic cerebral perfusion. Possible beneficial effects on pericontusional perfusion, brain
edema, and contusion volume were investigated in rats subjected to controlled cortical impact (CCI).
Male Sprague-Dawley rats (n ? 60) anesthetized with isoflurane were subjected to a left temporo-
parietal CCI. Thereafter, rats were randomized to receive HHES (10% hydroxyethylstarch, 7.5%
NaCl) or physiological saline solution (4 mL/kg body weight) intravenously. Mean arterial blood
pressure (MABP) and intracranial pressure (ICP) were determined before and following CCI, af-
ter drug administration and 24 h later. Regional pericontusional cortical perfusion was determined
by scanning laser Doppler flowmetry before CCI, and 30 min, 4 and 24 h after injury. At 24 h brain
swelling and water content were measured gravimetrically. At 7 days, cortical contusion volume
was determined planimetrically. MABP was not influenced by HHES. ICP was significantly de-
creased immediately after HHES infusion (5.7 ? 0.4 vs. 7.1 ? 1.0 mm Hg; p ? 0.05). Pericontusional
cortical perfusion was significantly decreased by 44% compared to pre-injury levels (p ? 0.05).
HHES significantly improved cortical perfusion at 4 h after CCI, approaching baseline values (85 ?
12%). While increased posttraumatic brain edema was not reduced by HHES at 24 h, cortical con-
tusion volume was significantly decreased in the HHES-treated rats at 7 days after CCI (23.4 ? 3.5
vs. 39.6 ? 6.2 mm3; p ? 0.05). Intravaneous administration of HHES within 15 min after CCI has
a neuroprotective potential, as it significantly attenuated impaired pericontusional perfusion and
markedly reduced the extent of induced structural damage.
Key words: brain edema; brain trauma; hyperosmotic-hyperoncotic solution; laser Doppler; small vol-
1Department of Neurosurgery, Charité, Virchow Medical Center, Humboldt University Berlin, Germany.
2Department of Neurosurgery, Ruprecht-Karls University, Heidelberg, Germany.
3Department Surgery, Division of Surgical Intensive Care Medicine, University Hospital Zurich, Switzerland.
which contributes to evolving structural and functional
deterioration observed within the first two posttraumatic
days. Reduced cerebral perfusion shows a strong regional
and temporal heterogeneity as observed under clini-
cal (Abdel-Dayem et al., 1998; Diringer et al., 2002;
McLaughlin and Marion, 1996; Yamakami et al., 1993)
and experimental conditions (Bryan et al., 1995; Thomale
et al., 2001, 2002).
In otherwise healthy and stable rats, cerebral perfusion
is progressively and markedly diminished in the peri-
contusional cortex reaching lowest values between 4 and
8 h after induction of a focal cortical contusion (Krop-
penstedt et al., 1999, 2000, 2003; Stover et al., 2000,
2003; Thomale et al., 2001, 2002). Within the following
24 h, pericontusional cortical perfusion is restored as mi-
crocirculatory stasis due to extensive clot formation
(Maeda et al., 1997; Thomale et al., 2001, 2002) is spon-
taneously resolved. While the contusion consists of se-
verely injured tissue with rapidly developing ischemia
characterized by blood flow values below 20 mL/100
g/min (Bryan et al., 1995; Kochanek et al., 1995), the
pericontusional regions are viable and considered pri-
marily salvageable. As recently shown, the reduced per-
fusion determined in the deep cortical layers below the
contusion accompanied by significantly decreased brain
tissue oxygen levels (ptiO2? 10 mm Hg) preceded the
secondary growth of the cortical contusion (Kroppenst-
edt et al., 2003). Thus, attenuating the pericontusionally
impaired perfusion is thought to protect the surrounding
primarily viable tissue and possibly prevent secondary le-
One current therapeutic approach under clinical con-
ditions is aimed at maintaining a cerebral perfusion pres-
sure (CPP) of 60–70 mm Hg to prevent evolving isch-
emia (Guidelines for Treatment of Severe Head Injury,
2000). However, experimental data clearly show that
pericontusional cortical perfusion is severely impaired at
a CPP of 70 mm Hg and that higher CPP values are re-
quired to restore normal perfusion values during the
acute posttraumatic phase (Kroppenstedt et al., 2000).
These high CPP values, however, can only be reached
by continuously infusing norepinephrine which, unfor-
tunately, is associated with a significant increase in
neuronal activity, extracellular glutamate, and intra-
parenchymal hemorrhage (Kroppenstedt et al., 2002; van
Landeghem et al., 2003).
Thus, one reasonable approach could be to improve
pericontusional cerebral perfusion without increasing
mean arterial blood pressure and hydrostatic capillary
OCAL TRAUMATIC BRAIN INJURY (TBI) is associated
with significantly impaired local cerebral perfusion,
pressure, which in the face of a damaged blood brain–bar-
rier (BBB), could aggravate underlying brain edema for-
mation and tissue injury. This could be achieved by sys-
temically infusing hyperosmotic and hyperoncotic
solutions, which mobilize intraendothelial and interstitial
water to expand and restitute the intravascular volume.
In this context, small volume resuscitation (SVR) using
a hyperosmolar–colloidal solution with a volume of 4
mL/kg body weight (Kreimeier et al., 1997) has been in-
troduced in the clinical treatment of patients with hem-
orrhagic shock as it rapidly restored impaired tissue per-
fusion (Holcroft et al., 1987; Kreimeier et al., 1997;
Mattox et al., 1991; Mazzoni et al., 1988; Vassar et al.,
Following hemorrhagic shock (Kramer et al., 1986;
Vollmar et al., 1994) and posttraumatic muscular lesions
(Mittlmeier et al., 2003), hyperosmotic and hyperoncotic
solutions restored impaired microcirculation related to
hemodilution-associated improved rheology, reduced
swelling of endothelial cells, and increased capillary di-
ameter. Following TBI, hyperoncotic/hyerosmolar solu-
tions restored impaired microcirculation and decreased
posttraumatic edema (Kempski et al., 1996; Qureshi and
Suarez, 2000; White and Likavec, 1992) by shifting free
water into the intravascular lumen, thereby reducing
posttraumatic endothelial swelling (Mazzoni et al., 1988)
and decreasing capillary resistance (Mittlmeier et al.,
2003). In addition, hemodilutive effects of SVR improve
rheological properties of the blood (Mittlmeier et al.,
2003). Furthermore, hyperoncotic/hyperosmotic solu-
tions reduced rolling and sticking of white blood cells
to the capillary wall in the early phase following exper-
imental brain injury and attenuate postischemic mi-
crovascular disturbances (Hartl et al., 1997; Nolte et al.,
HyperHaes™ (HHES) is a hyperoncotic hyperosmo-
lar agent combining 7.5% saline with 10% hydroxy-
ethyl starch with an osmolality of 2400 mosom/L,
which exceeds the normal blood osmolality by eight-
fold. In various clinical and experimental settings of hy-
povolemic shock, soft tissue trauma, and cerebral ve-
nous occlusion, HHES has been shown to improve
impaired microcirculation (Heimann et al., 2003;
Kreimeier et al., 1997; Mittlmeier et al., 2003; Vollmar
et al., 1994).
The present study was designed to determine if single
systemic administration of HHES improves attenuated
pericontusional cortical perfusion during the early phase
following an experimentally induced focal cortical con-
tusion and if HHES reduces intracranial pressure and tis-
sue damage reflected by edema formation and cortical
contusion volume determined at 24 h and 7 days, re-
THOMALE ET AL.
MATERIALS AND METHODS
Anesthesia and Traumatic Brain Injury
Following approval of the study protocol by the local
ethic committee of the Humboldt University 60 sponta-
neously breathing Sprague Dawley rats (300–350 g)
anesthetized with isoflurane/N2O/O2(isoflurane: 1.6–2.2
vol%; N2O: 0.5 L/min, O2: 0.3 L/min) were subjected to
a controlled cortical impact (CCI) injury as previously
described (Kroppenstedt et al., 1999, 2000, 2003; Stover
et al., 2000, 2003; Thomale et al., 2001, 2002). For this,
rats were positioned in a stereotaxic holder and a left pari-
etotemporal craniectomy (11 ? 8 mm) was performed
along the anatomical guidelines outlined by the sagittal,
lambdoid and coronal sutures and the zygomatic arch.
Then a cortical contusion was induced by pneumatically
accelerating a 5-mm bolt to a velocity of 7 m/sec (5.2
bar) with a penetration depth of 1 mm and a contact time
of 300 msec. The bolt was positioned at a 45 degree an-
gle perpendicular to the surface of the cerebral convex-
ity at approximately 3 mm lateral to the sagittal suture.
With these settings, the dura remained intact.
Following CCI, the scalp was sutured, arterial and ve-
nous lines were removed and the rats were returned to their
cages until further evaluation at 4 and 24 h and 7 days.
For each investigated time point, rats were anesthetized
with isoflurane/ N2O/ O2, maintaining administered isoflu-
rane concentration at 1.8 vol% at all time points.
Mean Arterial Blood Pressure, Arterial Blood
Gases, and Body Temperature
Cannulating the left femoral artery allowed to monitor
mean arterial blood pressure (MABP) and determine arte-
rial blood gases (ABG). Repetitive cannulation of the same
femoral artery before trauma, at 30 min, and 4 and 24 h
after CCI was feasible and well tolerated by all rats, as
previously reported (Stover et al., 2003). Cannulation was
performed using a surgical microscope and special care
was taken not to damage the femoral nerve. Following each
measurement the arterial catheter was removed, the scalp
was sutured, and rats were returned to their cages. During
anesthesia, rectal temperature was maintained at 37 ?
0.5°C using a homeothermic heating pad.
Intracranial Pressure (ICP) and Cerebral
Perfusion Pressure (CPP)
ICP was measured by positioning an ICP microsensor
(Codman) in the contralateral hemisphere (relative to
Bregma: 0; ?4 mm) (Stover et al., 2003) which allowed
to mathematically determine changes in cerebral perfu-
sion pressure (CPP) based on the following equation:
CPP ? MABP ? ICP.
Laser Doppler Flowmetry (LDF)
Regional cerebral blood flow (rCBF) in the pericontu-
sional area was measured by Laser Doppler Flowmetry
(LDF, DRT4; Moor Instruments, Devon, UK) and dis-
played in arbitrary Laser Doppler units (LDU). For this,
a Laser Doppler needle probe with a diameter of 800 µm
attached to the micromanipulator of a stereotaxic frame
at a distance of 1 mm from the intact dura was moved in
0.2-mm steps from the occipital to frontal pole over a to-
tal distance of 8 mm parallel to the sagittal suture and
medial to the contusion. In this position cortical perfu-
sion is determined at the depth of 2.5 mm at the site of
the impact and in the pericontusional cortex. To assure
standardized measurements, we marked the posterior rim
of the craniectomy by drilling a notch 2 mm lateral to the
sagittal suture. This procedure allowed to investigate
identical areas in all rats at different time points. For each
time point, 40 measurements were performed. Acquired
data of cortical perfusion was used to assess relative
changes over time. Changes were determined based on
the mean of the summed median values of each scan per
rat and displayed in percent to pre-trauma levels. In ad-
dition, regional alterations in relative LDU values were
analyzed by histograms.
Within 15 min following CCI, rats were randomized
to either receive physiological saline solution (NaCl) or
HHES with a total volume of 4 mL/kg body weight for
10 min via the femoral vein. Changes in pericontusional
cortical perfusion were assessed before and at 4 and 24
h following CCI in 10 animals. At 24 h following CCI,
brain edema was determined gravimetrically in 24 ani-
mals. In these animals, ICP was monitored before trauma,
before and following infusion, and 24 h after trauma. At
7 days, contusion volume was planimetrically quantified
in 16 animals.
Posttraumatic Brain Edema
At 24 h following CCI, rats were killed by exsanguina-
tion and brains were removed to gravimetrically determine
posttraumatic hemispheric water content and brain
swelling. The dissected hemispheres were weighed before
and after drying at 100°C for 24 h to assess wet (WW) and
dry weight (DW) as described previously (Kroppenstedt et
al., 2000, 2002, 2003; Stover et al., 2000, 2003):
? (WWL/R? DWL/R)/WWL/R] * 100
Swelling [%] ? [(WWL? WWR)/WWR] * 100
SMALL VOLUME RESUSCITATION AFTER CCI
Cortical Contusion Volume
At 7 days following trauma, the removed brains were
cut in 1.3-mm slices beginning at the occipital pole us-
ing a commercially available matrix for rat brain (Brain
Blocker, AgnTho’s AB, Lidingö, Sweden). The brain
sections were incubated in 2% triphenyltetrazolium-chlo-
ride (TTC) solution at 37°C for 30 min and recorded pho-
tographically. The contusion area was determined off-
line using a computerized image analysis system (Sigma
Scan®3.0, Jandel Scientific, Erkrath, Germany). Multi-
plying the average area from the front and back of each
slice by its thickness and adding all slices allowed us to
determine the cortical contusion volume as previously de-
scribed (Stover et al., 2000).
Data are expressed as mean ? SEM. Changes over
time (LDF, ICP, MABP, CPP, arterial blood gases) were
evaluated for statistical significance by analysis of vari-
ances (ANOVA) on ranks for multiple comparisons.
Statistical analysis of brain edema and cortical contu-
sion volume was performed by Student’s t-test. (Sigma
Stat®3.0; Jandel Scientific, Erkrath, Germany). Differ-
ences were rated significant at p ? 0.05.
Arterial blood gases remained within physiological
limits at all time points. Hemoglobin was significantly
reduced immediately after HHES infusion versus rats re-
ceiving NaCl and remained decreased thereafter (Table
1). Weight loss during the first 24 h and 7 days after CCI
was similar in all rats (NaCl: ?4.7 ? 0.5% [24 h];
?5.0 ? 2% [7 days]; HHES: ?4.8 ? 0.4% [24 h];
?3.1 ? 1.2% [7 days]).
MABP, ICP, and CPP
MABP and CPP were similar in HHES-treated and
control rats (Table 1). Following CCI, ICP was increased,
reaching highest values at 24 h in control rats. Follow-
ing HHES infusion, ICP was significantly reduced com-
pared to control rats and remained decreased at 24 h with-
out, however, reaching statistical significance (Table 1).
THOMALE ET AL.
TABLE 1. CHANGES IN ARTERIAL BLOOD GASES, MABP, ICP, AND CPP BEFORE CCI, BEFORE AND IMMEDIATELY AFTER
INFUSION OF HHES OR NACL, AND 24 H LATER DETERMINED IN 13 RATS RECEIVING NACL AND 13 HHES-TREATED RATS
TreatmentBefore CCl Before infusion After infusion24 h later
109.8 ? 8.3
105.2 ? 8.9
105.8 ? 9.6
104.9 ? 8.6
111.3 ? 9.8
96.7 ? 7.6
129.6 ? 8.0
116.1 ? 10.9
34.5 ? 2.1
37.9 ? 1.9
34.6 ? 2.1
37.3 ? 2.9
39.2 ? 2.0
42.3 ? 2.6
35.7 ? 1.5
33.4 ? 1.0
7.46 ? 0.01
7.43 ? 0.03
7.45 ? 0.02
7.42 ? 0.03
7.40 ? 0.01
7.35 ? 0.05
7.48 ? 0.02
7.49 ? 0.02
1.24 ? 0.9
0.65 ? 0.6
0.18 ? 0.5
?0.63 ? 0.7
0.04 ? 0.6
?1.5 ? 0.4
2.71 ? 0.9
1.8 ? 0.6
12.9 ? 0.5
13.4 ? 0.6
12.5 ? 0.3
12.6 ? 0.3
12.0 ? 0.4
10.9 ? 0.4b
10.4 ? 0.6a
10.4 ? 0.9
MABP (mm Hg) NaCl
85.1 ? 2
89.7 ? 2
84.3 ? 4
86.0 ? 3
80.4 ? 2
77.1 ? 4
90.6 ? 3
89.8 ? 3
ICP (mm Hg)NaCl
5.4 ? 0.7
6.6 ? 0.7
7.7 ? 1.2a
8.2 ? 0.9
7.1 ? 1.0
5.7 ? 0.4b
8.8 ? 1.9a
6.3 ? 0.7
CPP (mm Hg) NaCl
79.7 ? 2
83.1 ? 1
76.6 ? 3
77.8 ? 2
73.3 ? 2
71.4 ? 4
81.8 ? 2
83.5 ? 2
ap ? 0.05 vs. baseline.
bp ? 0.05 vs. NaCl.
BE, base excess, Hb, hemoglobin.
Pericontusional Cortical Perfusion
Following CCI, pericontusional cortical perfusion de-
termined by LDF was significantly decreased by 43.5 ?
6.2% in control rats at 4 h after CCI compared to pre-
trauma levels (p ? 0.05, Fig. 1).
Early HHES infusion started within 15 min after CCI
significantly attenuated the CCI-induced impaired peri-
contusional cortical perfusion (?14.8 ? 12.1%; p ?
0.05; Fig. 1). Over time, the hypoperfusion observed at
4 h progressed to increased perfusion levels at 24 h fol-
lowing CCI which was similar in both groups (Fig. 1).
As determined by the regional distribution pattern, cor-
tical perfusion was predominantly increased in the frontal
and occipital areas adjacent to the contusion (Fig. 2). Sub-
dividing the scanned stretch into equal parts revealed the
highest increase in regional perfusion within the frontal
pericontusional cortex at 4 h after HHES infusion
Posttraumatic Brain Edema
At 24 h after CCI, hemispheric swelling was reduced
in HHES-treated rats compared to rats receiving NaCl
(Table 2) without, however, reaching statistical signifi-
Water content in the traumatized hemisphere was sig-
nificantly increased in all animals compared to the non-
traumatized hemisphere. In the HHES group, water con-
tent in the traumatized hemisphere only showed a
tendency to reduced levels (Table 2). Water content in
the non-traumatized hemispheres was similar in all rats.
Cortical Contusion Volume
At 7 days after CCI, TTC staining delineated a well-
defined margin of the lesioned brain tissue. Cortical con-
tusion volume was significantly reduced in the HHES-
treated animals compared to controls (23.4 ? 3.5 vs.
39.6 ? 6.2 mm3, p ? 0.05; Fig. 3).
Following CCI, early single systemic infusion of
HHES in hemodynamic stable and otherwise uninjured
rats significantly attenuated impaired pericontusional
cortical perfusion, reduced ICP and decreased cortical
contusion volume without, however, influencing brain
Time Point of Infusion
In the present study, HHES was administered within
15 min after CCI, a time frame that does not necessarily
reflect the clinical situation as healthcare professionals
usually arrive at the accident scene within 30–90 min.
However, our previous characterization using intravital
microscopy combined with Laser Doppler flowmetry re-
SMALL VOLUME RESUSCITATION AFTER CCI
the pericontusional cortex expressed in percent to pre-injury lev-
els. HHES (black circles) significantly attenuated the impaired
cortical perfusion observed in control rats (white circles) at 4 h
after CCI. Over time, the early hypoperfusion was followed by
hyperperfusion at 24 h in both groups. *p ? 0.05 versus pre-in-
jury level and 4 h; ?p ? 0.05 HHES versus NaCl at 4 h.
Temporal profile of changes in regional perfusion in
sion values determined in different areas of the injured hemi-
sphere. The HHES- induced increase in pericontusional corti-
cal perfusion (black bars) was mostly sustained in the adjoining
occipital and frontal parts of the scanned area compared to con-
trols (white bars). *p ? 0.01; **p ? 0.001.
Regional alterations in relative laser Doppler perfu-
vealed that the ensuing impairment of pericontusional
cortical microcirculation and perfusion starts within
minutes after inducing a focal cortical contusion and is
progressively aggravated during the following hours
(Thomale et al., 2001, 2002). The half-life of HHES is
approximately 4–6 h (Dieterich, 2003) and coincides
with the crucial phase characterized by maximally re-
duced perfusion within the pericontusional cortex.
Thus, the chosen time point of infusion is suitable and
adequate to determine a relevant and potentially bene-
ficial effect of HHES. Future studies are required to de-
termine a therapeutic window and also rule out poten-
tial deleterious effects of repetitive infusions as
performed in the clinical setting, as, for example, hy-
pernatremia, disturbed coagulation, and sustained
Absent Reduction in Edema Formation
The discrepancy between the long-term protective ef-
fect reflected by a significantly reduced cortical contu-
sion volume at 7 days and the missing short-term effect
of reducing brain edema at 24 h after CCI could be re-
lated to methodological issues as well as pharmacody-
namic influences. In the present study, brain swelling and
water content were determined by investigating changes
in net water accumulation of the entire hemisphere. Since
the induced contusion remains confined to the cortex
without involving subcortical structures (Stroop et al.,
1998) and only involves approximately 50% of the ipsi-
lateral cortex, it could very well be that a significant re-
gional edema-reducing effect was missed by weighing
the entire hemisphere. The infused hyperosmolar/hyper-
oncotic solution binds free water and thus reduces the in-
terstitial water load which for the damaged brain attenu-
ates vasogenic edema formation. However, a damaged
blood–brain barrier present within the cortical contusion
could in theory entrap extravasated hetastarch with a mol-
ecular weight of approximately 200 kDa. This, in turn,
could increase local edema formation, which then masks
a potential reduction in water content in adjacent corti-
Pharmacodynamic Properties of HHES
The employed HyperHaes™ (HHES) consists of 10%
hydroxyethyl starch 200,000 plus 7.5% saline. Each com-
pound exerts characteristic effects which are potentiated
once they are combined.
For fluid resuscitation practiced daily under clinical
conditions, colloid solutions (e.g., hydroxyethyl starch,
dextrans, albumin) are superior to crystalloid solutions
(e.g., NaCl, Lactated Ringers solution) as they expand
the intravascular compartment without loading the inter-
stitial space and thus counteract ensuing extracellular
edema formation (Rizoli, 2003). In addition, smaller vol-
THOMALE ET AL.
TABLE 2. CHANGES IN HEMISPHERIC SWELLING AND WATER
CONTENT DETERMINED AT 24 H FOLLOWING CCI
Water content (%)
Swelling (%) Right hemisphereLeft hemisphere
8.9 ? 0.6
8.3 ? 0.3
78.63 ? 0.1
78.67 ? 0.1
80.1 ? 0.08
79.95 ? 0.05
HHES did not significantly influence hemispheric swelling or
HHES significantly decreased the cortical contusion volume on day 7 following CCI. *p ? 0.05 versus NaCl.
umes are required to achieve similar resuscitation end-
points with an estimated ratio of 1:7 to 1:10 (Orlinsky
et al., 2001).
Hetastarch, similar to glycogen found within human
cells, consists of 16 glucose rings, which, upon modifi-
cation of molecular weight, molar substitution, and num-
ber and position of hydroxyethyl groups, results in a
variety of HES solutions with charateristic properties
(Dieterich, 2003). The employed mean molecular weight
HES (200 kDa) protects the endothelium from activated
leukocyte-mediated cell damage by reducing the expres-
sion of intercellular adhesion molecule–1 and E-selectin-
1 (Dieterich, 2003).
Hypertonic 7.5% NaCl with an osmolality of 2400
mosm/L increases the intravascular volume several fold
the volume infused, increases cardiac contractility, re-
duces peripheral vascular resistance (Kien et al., 1991),
improves microcirculatory hemodynamics, attenuates
posttraumatic inflammatory responses at the endothelial
cells (Pascual et al., 2003) which is crucial for the de-
velopment of multi-organ damage, and has been reported
to increase survival in head-injured patients with a Glas-
gow Coma Score of ?8 compared to patients receiving
Lactated Ringers solution (Vassar et al., 1993). Combin-
ing hypertonic NaCl with colloid solutions extends its in-
Administration of hypertonic-hyperosmotic solutions
might increase plasma osmolarity, elevate plasma chlo-
ride anion load and reduce serum potassium levels pos-
sibly causing hyperchloremic acidosis and cardiac ar-
rhythmia, respectively (Shackford et al., 1987; Vassar
et al., 1990). In critically injured and dehydrated or
high-risk patients, sustained hypertonic-hyperosmolar
load might induce renal failure (Holcroft et al., 1987).
Thus, administration of hypertonic-hyperosmotic solu-
tions needs to be closely controlled under clinical con-
Perfusion and Inflammatory Response
To date, pharmacodynamic studies of infused hyper-
oncotic/hyperosmolar solutions have been predominantly
conducted in models of acute ischemic brain injuries re-
vealing improved cerebral blood flow in a canine hem-
orrhagic shock model (Prough et al., 1991a,b), reduced
intracranial pressure and maintained somatosensory
evoked potentials following global cerebral ischemia in
rabbits (Kempski et al., 1996), and diminished cerebral
infarct size resulting from improved regional cerebral
blood flow and reduced no-flow/low-flow areas follow-
ing cortical vein occlusion in rats (Heimann et al., 2003).
However, effects of HHES on cortical perfusion and tis-
sue damage have not yet been investigated following ex-
perimental TBI. Induction of a focal cortical contusion
with the CCI model results in changes which can be in-
fluenced by HHES. In this context, we have observed
sustained upregulation of endothelial ICAM-1 and in-
creased presence of neutrophilic granulocytes in the in-
jured cortex within the first hours following CCI (Stover,
unpublished results) coinciding with severely compro-
mised pericontusional cortical microcirculation (Thomale
et al., 2002) characterized by endothelial swelling and
sustained clot formation (Thomale et al., 2002; Krop-
penstedt et al., 2003). In line with previous reports fol-
lowing experimental cerebral ischemia (Heimann et al.,
2003), HHES significantly improved posttraumatic peri-
contusional perfusion during the acute phase considered
most vulnerable to secondary injuries (Cherian et al.,
1996; Kroppenstedt et al., 1999). Maintaining and restor-
ing adequate cortical perfusion in addition to beneficially
influencing inflammatory processes could account for the
observed tissue preservation as reflected by the decreased
cortical contusion volume measured at 7 days following
CCI. This stresses the need to prevent impaired perfusion
early after TBI.
ICP and Brain Edema
According to the Kelly Monro doctrine, a small in-
crease in intracranial volume will result in a larger ele-
vation in ICP in the presence of an underlying cerebral
injury and limited compliance. Such an increase in in-
tracranial volume can be caused, for example, by under-
lying brain edema or sustained cerebral blood volume
(hyperemia). Under the present experimental conditions,
the observed increase in ICP during the acute phase is
predominantly related to evolving edema formation while
the elevated ICP at 24 h could be caused by maximal
edema formation and increased cerebral blood volume re-
flected by sustained LDF values exceeding pre-injury
values by 50%.
The significant decrease in ICP following HHES in-
fusion observed in the presently studied rats subjected to
CCI is in line with results obtained following global cere-
bral ischemia (Kempski et al., 1996), which is thought to
be related to the hyperosmolar/hyperoncotic abilities of
HHES shifting water from the extracellular space to the
intravascular compartment and thereby reducing under-
lying edema formation. This reduction in ICP, however,
was only transient as ICP increased to similar values seen
in control rats at 24 h after CCI. Thus, repetitive HHES
infusions might be required to counteract the underlying
edema formation which continuously progresses within
the first 24 h before reaching its maximal extent at 24
and 48 h after CCI (Stover et al., 2000).
SMALL VOLUME RESUSCITATION AFTER CCI
The present data suggest that early single systemic in-
fusion of HHES restores impaired regional perfusion in
the pericontusional cortex at 4 h following CCI in he-
modynamically and otherwise healthy rats. It appears
that this transient beneficial effect is crucial in attenuat-
ing evolving secondary tissue damage, as the cortical
contusion volume determined 7 days later was signifi-
To date, only patients presenting with hemodynamic
instability will receive plasma expanders (e.g., HES),
while hemodynamically stable patients are routinely
treated with crystalloid solutions. When carefully trans-
ferred to the clinical situation, these data suggest that
early administration of HHES at the accident scene, even
in hemodynamically stable patients, could attenuate
evolving impaired perfusion.
This work was supported in parts by research grants
from the Charitè, Humboldt University, Berlin
(89531006/01 and 89531053/01 to J.F.S.) and the Re-
search Award 2001 of the Deutsche Gesellschaft fuer
Neurotraumatologie und Klinische Neuropsychologie
(DGNKN) to Dr. John F. Stover.
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Address reprint requests to:
Ulrich-Wilhelm Thomale, M.D.
Department of Neurosurgery
Charité, Virchow Medical Center
Augustenburger Platz 1
D-13353 Berlin, Germany
THOMALE ET AL.